Notch1 cardioprotection in myocardial ischemia/reperfusion involves reduction of oxidative/nitrative stress
Notch1 cardioprotection in myocardial ischemia/reperfusion involves reduction of oxidative/nitrative stress
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DOI：
10.1007/s00395-013-0373-x
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发表时间：
2013-09-01
影响因子：
9.5
通讯作者：
Tao, Ling
中科院分区：
文献类型：
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作者：
Pei, Haifeng;Yu, Qiujun;Tao, Ling
氧化/硝化应激在心肌缺血/再灌注（MI/R）损伤中起重要作用。Notch 1参与了心肌发生和心肌对肥厚性应激反应的调节，但Notch 1信号通路在心肌梗死/再灌注中的作用尚不清楚。本研究旨在确定Notch 1在MI/R中的作用，并研究Notch 1是否具有心脏保护作用。通过心肌内注射递送Notch 1特异性小干扰RNA（siRNA，20 μ g）或Jagged 1（Notch配体，12 μ g）。注射后48小时，小鼠经受30分钟的心肌缺血，随后进行3小时（用于细胞凋亡和氧化/硝化应激）、24小时（用于梗死面积和心脏功能）或2周（用于心脏纤维化和功能）的再灌注。心脏特异性Notch 1基因敲低导致I/R损伤显著加重，表现为梗死面积扩大、心功能降低、心肌细胞凋亡增加和心脏纤维化。Notch 1的下调增加了诱导型NO合酶（iNOS）和gp（91 phox）的表达，增加了NO代谢物和超氧化物及其细胞毒性反应产物过氧亚硝酸盐的产生。此外，Notch 1阻断还减少了内皮NO合酶（eNOS）和Akt的磷酸化，并增加了PTEN的表达，这是一种参与Akt磷酸化调节的关键磷酸酶。此外，通过Jagged 1激活Notch 1或给予过氧亚硝酸盐清除剂可减少过氧亚硝酸盐的产生并减轻MI/R损伤。这些数据表明，Notch 1信号通路部分通过PTEN/Akt介导的抗氧化和抗硝化作用来保护MI/R损伤。
Oxidative/nitrative stress plays an important role in myocardial ischemia/reperfusion (MI/R) injury. Notch1 participates in the regulation of cardiogenesis and cardiac response to hypertrophic stress, but the function of Notch1 signaling in MI/R has not been explored. This study aims to determine the role of Notch1 in MI/R, and investigate whether Notch1 confers cardioprotection. Notch1 specific small interfering RNA (siRNA, 20 mu g) or Jagged1 (a Notch ligand, 12 mu g) was delivered through intramyocardial injection. 48 h after injection, mice were subjected to 30 min of myocardial ischemia followed by 3 h (for cell apoptosis and oxidative/nitrative stress), 24 h (for infarct size and cardiac function), or 2 weeks (for cardiac fibrosis and function) of reperfusion. Cardiac-specific Notch1 knockdown resulted in significantly aggravated I/R injury, as evidenced by enlarged infarct size, depressed cardiac function, increased myocardial apoptosis and cardiac fibrosis. Downregulation of Notch1 increased expression of inducible NO synthase (iNOS) and gp(91phox), enhanced the production of NO metabolites and superoxide, as well as their cytotoxic reaction product peroxynitrite. Moreover, Notch1 blockade also reduced phosphorylation of endothelial NO synthase (eNOS) and Akt, and increased expression of PTEN, a key phosphatase involved in the regulation of Akt phosphorylation. In addition, activation of Notch1 by Jagged1 or administration of peroxynitrite scavenger reduced production of peroxynitrite and attenuated MI/R injury. These data indicate that Notch1 signaling protects against MI/R injury partly though PTEN/Akt mediated anti-oxidative and anti-nitrative effects.